Enantioselective and Domino Intermolecular Stetter Reactions
This thesis describes three advances in the field of NHC-catalyzed reactions. In particular, a complementary method for the enantioselective intermolecular Stetter reaction as well as the development of the first domino transformations employing the Stetter reaction as the initial step is presented. The first chapter of this work briefly introduces the discovery and use of N-heterocyclic carbenes as organocatalysts, followed by a short description of the Stetter reaction. In addition, major achievements on the enantioselective intermolecular version of this transformation are also described. To conclude the chapter, a review describing early investigations and development of novel domino reactions employing acyl anion equivalents as the initial step. Chapter two of this thesis describes a recently developed highly enantioselective synthesis of α,δ-diketoesters via an intermolecular Stetter reaction. Using this method, heteroaromatic and electron-poor aromatic aldehydes undergo conjugate addition onto γ-aryl-α,β-unsaturated-α-ketoesters, furnishing the Stetter products in moderate to excellent yields and enantioselectivities. Additionally, the synthetic usefulness of these adducts is showcased by the preparation of multiple synthetic building blocks, such as N-protected α-aminoesters, disubstituted δ-lactones, and trisubstituted tetrahydrofuran derivatives. The third chapter is a good illustration of the development, study, and applications of the first domino reaction using the Stetter reaction as the initial step. This novel methodology furnishes trisubstituted indanes, featuring three contiguous stereogenic centres. The success of this transformation relies on the enolate intermediate generated from a Stetter reaction, which is used to perform a subsequent conjugate addition on a different Michael acceptor. The products, obtained employing this protocol are later utilized for the synthesis of complex polycyclic pyrroles. Finally, the fourth chapter of this thesis exemplifies how the endeavors in research for developing new methodologies sometimes lead to exciting discoveries. This section describes the finding of a novel and efficient approach for the synthesis of carbocyclic spiro compounds. This method consists in the homo- or cross-dimerization of o-formylchalcone derivatives producing spiro bis-indanes in a single operation via domino Stetter–aldol–Michael and Stetter–aldol–aldol processes. This protocol was used to prepare analogs of the core backbone present in fredericamycin A, a complex polysubstituted aromatic spiro bis-indane which exhibits antitumor antibiotic properties.
DegreeDoctor of Philosophy (Ph.D.)
CommitteeGleason, James; Covello, Patrick; Majewski, Marek; Ward, Dale E.
Copyright DateDecember 2011
acyl anion equivalents